Chasing Men on Fire

The Story of the Search for a Pain Gene

Stephen G. Waxman

Publication Year: 2018

Two soldiers, both with wounds injuring the same nerve, show very different responses: one is disabled by neuropathic pain, unable to touch the injured limb because even the lightest contact triggers excruciating discomfort; the other notices numbness but no pain at all. Could the difference lie in their genes? In this book, described in the foreword by Nobel Laureate James Rothman as "so well written that it reads like a detective novel," Stephen Waxman recounts the search for a gene that controls pain -- a search spanning more than thirty years and three continents. The story moves from genes to pain-signaling neurons that scream when they should be silent to people with a rare genetic disorder who feel they are on fire. Waxman explains that if pain-signaling neurons are injured by trauma or disease, they can become hyperactive and send pain signals to the brain even without external stimulus. Studying the hyperactive mutant pain gene in man on fire syndrome has pointed the way to molecules that produce pain more broadly within the general population, in the rest of us. Waxman's account of the many steps that led to discovery of the pain gene tells the story behind the science, of how science happens.

Cover

Title Page, Copyright, Dedication

CONTENTS

FOREWORD

If you are interested in how scientific medicine is done, this is cause enough to read this book. Whether
you are a layperson or a scientist, if you are interested in the brain and the nervous system, you will
also be interested because Waxman explains the ideas and their history so clearly and simply and yet
accurately. Indeed the book is so well written that it reads like a detective novel, making it irresistible
to turn the next page (or swipe the screen of your Kindle).

The explicit focus is Waxman’s lifelong pursuit as a neurologist of how pain arises, how we can
better understand it, and how new medicines for pain can be developed to treat it. He has had remarkable
success in this pursuit initially through the discovery of a gene that controls pain. Waxman’s...

PREFACE

This volume had its origin when several people suggested that I write a book on my search for a pain
gene, a gene that controls pain sensibility in humans. Each suggested that the topic was timely, but
each imagined a book for a different audience. A colleague forwarded the idea of a text for scientistsin-training
and physicians-in-training, another suggested a book for a lay readership interested in pain,
and still another suggested a volume for scientists and physicians. In the end, after consulting with
colleagues, book publishers, and editors, and ultimately with Bob Prior of MIT Press, I decided to
take a hybrid approach, combining some of my primary papers with commentaries that place them in
a broader context in order to reach all these audiences....

ACKNOWLEDGMENTS

None of us lives or works in a vacuum, and I certainly have not. I owe an immense debt to my teachers
and mentors. These have included J. David Robertson and Howard Hermann of Harvard Medical
School and J. Z. Young of University College London. My mentors at the Albert Einstein College of
Medicine, neurophysiologist Dominick Purpura and electron microscopist George Pappas, showed by
example that neuroscience is not constrained by any single set of methods but can, on the contrary, be
truly multidisciplinary; Michael Bennett, also a professor at Einstein, provided an example of rigor in
electrophysiology and, both at Einstein and during summers at the Marine Biological Laboratory in
Woods Hole, pointed my research compass in the direction of axons. As a medical student, I also had...

I DISSECTING GOD’S MEGAPHONE

1 DISSECTING GOD’S MEGAPHONE: THE SEARCH FOR A PAIN GENE

Each one of us, at some time during our lives, experiences physical pain. Although C. S. Lewis, in
his much-cited comment, was referring to spiritual pain, physical pain can also be considered to be
God’s megaphone. The sensation of physical pain—“My body hurts!”—is nearly universal. When
pain is transient, it can protect us, warning us to withdraw from a threatening situation. Pain can also
teach us—most children rapidly learn, for example, not to touch hot objects. But pain is not always
helpful. If pain persists after a painful stimulus is no longer there and becomes chronic, it can invade
a life and change it....

2 SHERRINGTON’S ENCHANTED LOOM AND HUXLEY’S SCIENCE FICTION

The human nervous system—our brain, spinal cord, and nerves—is the world’s most complex computer.
There are more than 100 billion nerve cells in the human brain and spinal cord, greater than the
number of stars within the Milky Way.

These nerve cells, called neurons by scientists, act as tiny transistors, or in some cases as integrated
circuits. They send electrical impulses to and fro along nerve fibers, termed “axons” by neuroscientists,
as the nervous system makes countless computations each second. In 1942, the pioneering British
neuroscientist Charles S. Sherrington referred in his book Man on His Nature to the active brain as...

II CHASING MEN ON FIRE: THE SEARCH

3 ALABAMA TO BEIJING … AND BACK

The search for the pain gene began in an Alabama neighborhood with a group of men and women
carrying groceries, talking with each other, tending to their children, or driving down the street. Ordinary,
at first glance. But, many of the people did not wear regular shoes. Some wore open toed sandals.
Others preferred not to wear anything on their feet, to walk barefoot on a cool tile floor, or in the cold
water that collected in puddles. The children avoided the playground. They sometimes missed school
days. And, if you spent time with these people, you might hear a person say, “I’m getting an attack.”
Then, the affected person would grimace, their feet turning bright red, as if they had been badly sunburned.
If asked, they would say that their feet, and sometimes their hands, felt as if they were on fire....

Although the physiological basis of erythermalgia, an
autosomal dominant painful neuropathy characterized by
redness of the skin and intermittent burning sensation of
extremities, is not known, two mutations of NaV1.7, a
sodium channel that produces a tetrodotoxin-sensitive,
fast-inactivating current that is preferentially expressed
in dorsal root ganglia (DRG) and sympathetic ganglia
neurons, have recently been identified in patients with
primary erythermalgia. NaV1.7 is preferentially expressed
in small-diameter DRG neurons, most of which are nociceptors,
and is characterized by slow recovery from...

Erythromelalgia is an autosomal dominant disorder characterized
by burning pain in response to warm stimuli or
moderate exercise. We describe a novel mutation in a
family with erythromelalgia in SCN9A, the gene that
encodes the NaV1.7 sodium channel. NaV1.7 produces
threshold currents and is selectively expressed within
sensory neurons including nociceptors. We demonstrate
that this mutation, which produces a hyperpolarizing shift
in activation and a depolarizing shift in steady-state inactivation,
lowers thresholds for single action potentials and
high frequency firing in dorsal root ganglion neurons.
Erythromelalgia is the first inherited pain disorder in...

4 AVALANCHE

Soon after we published the functional analysis of the first NaV1.7 mutations from patients with erythromelalgia,
I was deluged with an avalanche of emails, letters, and telephone calls from around the
world. They were from people with chronic pain. Some of these people had erythromelalgia, and some
of them had mutations of NaV1.7 that we had not seen before. Here were new clues. But there also
were entreaties, requests for help. Especially touching were the enquiries from parents of children in
pain. In the beginning, I felt nearly helpless. I was navigating a large, complex sea.

We were looking for rare experiments of nature in which the gene for NaV1.7 had gone awry, with
the hope that each new genetic mistake would teach us something new. To do this, we established a...

THE NaV1.7 SODIUM CHANNEL: FROM MOLECULE TO MAN

The voltage-gated sodium channel NaV1.7 is preferentially
expressed in peripheral somatic and visceral sensory
neurons, olfactory sensory neurons and sympathetic ganglion
neurons. NaV1.7 accumulates at nerve fibre endings
and amplifies small subthreshold depolarizations, poising
it to act as a threshold channel that regulates excitability.
Genetic and functional studies have added to the evidence
that NaV1.7 is a major contributor to pain signalling in
humans, and homology modelling based on crystal structures
of ion channels suggests an atomic-level structural
basis for the altered gating of mutant NaV1.7 that causes...

5 TWO SIDES OF ONE COIN

A mutation—a change in a single gene—is termed “pathogenic” when it alters the gene product in a
way that causes disease. Within the human genome, there are more than 20,000 genes. Each one of the
cells within our body contains all of these 20,000 genes. Yet many mutations selectively impact some
tissues or cell types, leaving others unaffected. An example is provided by sickle cell anemia. In this
hereditary disorder, a mutation of the HBB gene results in production of an abnormal form of β-globin
which is a component of hemoglobin, the iron-containing protein that carries oxygen within the blood
from the lungs to other tissues throughout the body. Hemoglobin is present only in red blood cells,...

A SINGLE SODIUM CHANNEL MUTATION PRODUCES HYPEROR HYPOEXCITABILITY IN DIFFERENT TYPES OF NEURONS

Disease-producing mutations of ion channels are usually
characterized as producing hyperexcitability or hypoexcitability.
We show here that a single mutation can produce
hyperexcitability in one neuronal cell type and hypoexcitability
in another neuronal cell type. We studied the functional
effects of a mutation of sodium channel NaV1.7
associated with a neuropathic pain syndrome, erythermalgia,
within sensory and sympathetic ganglion neurons, two
cell types where NaV1.7 is normally expressed. Although
this mutation depolarizes resting membrane potential in
both types of neurons, it renders sensory neurons hyperexcitable
and sympathetic neurons hypoexcitable. The...

6 EAVESDROPPING

Imagine trying to eavesdrop on a room full of people by thrusting a microphone, attached to a ramrod
the size of telephone pole, through the wall. Although this technique of listening might allow one to
hear some noises, the message would not be representative of what normally goes on within that room.
Our intrusive microphone would blatantly disrupt any conversation. That is the type of challenge that
is faced by neurophysiologists who wish to study the details of the electrical activity within single
nerve cells. These cells measure, on average, less than 30 or 40 microns across, and in many cases,
have a diameter of less than 20 microns, one-fiftieth of a millimeter and a fraction of the breadth of a
human hair. Compounding the challenge, the electrical signals are tiny, ranging from 1/10 of a volt at...

The link between sodium channel NaV1.7 and pain has
been strengthened by identification of gain-of-function
mutations in patients with inherited erythromelalgia
(IEM), a genetic model of neuropathic pain in humans. A
firm mechanistic link to nociceptor dysfunction has been
precluded because assessments of the effect of the mutations
on nociceptor function have thus far depended on
electrophysiological recordings from dorsal root ganglia
(DRG) neurons transfected with wild-type (WT) or mutant
NaV1.7 channels, which do not permit accurate calibration
of the level of NaV1.7 channel expression. Here, we report
an analysis of the function of WT NaV1.7 and IEM L858H ...

III BEYOND THE SEARCH: EXPANDING HORIZONS

7 TWISTED NERVE: A GANGLION GONE AWRY

The man on fire syndrome is very rare. Neuropathic pain is not. It occurs commonly in disorders as
diverse as traumatic limb amputations, nerve or nerve root compression, and peripheral neuropathy
due to many causes. The central molecular player in inherited erythromelalgia, NaV1.7, is pivotal in
these disorders too.

The eminent nineteenth-century physician Silas Weir Mitchell—one of the founders of the American
Neurological Association—holds a place of special interest to military historians because he tended to
wounded soldiers on the Civil War battlefields. At that time, amputation of the injured limb was all
that was available to treat bullet wounds, and the concept of the ambulance—initially just a wagon to...

Injury to peripheral nerves associated with
trauma, amputation, compression, or surgery
can lead to the formation of painful neuromas,
tangled masses of blind-ending axons, and proliferating
connective tissue.1
In humans, these
neuromas can be debilitating, causing chronic
and severe pain, which is frequently refractory
to medical treatment. Axons in both experimental
and human neuromas have been shown...

8 CROSSING BORDERS

Popular legend has it that when Willie Sutton was asked why he robbed banks, he said “Because that’s
where the money is.” I have sometimes been asked why I have worked together with researchers in
Europe and Asia. Why travel thousands of miles for a collaboration when there are experts next door?
The short answer is “Because those are the collaborations that worked.” But that raises the following
questions: What is a fruitful collaboration? How can one make it happen?

Scientific collaborations are driven by need or opportunity. My interest in finding pain genes, and
my need to find the right patients, arose from watching my father spend the last years of his life sedated
by the opiate medications that were used—unsuccessfully—in an attempt to treat the neuropathic pain...

9 FROM ZEBRAS TO HORSES

A common admonition at rounds on the wards of teaching hospitals is “when you hear hoofbeats, think
of horses,” to which the attending physician might add “and don’t limit your thoughts to zebras.”
Zebras, in this setting, refer to rare diseases, while horses stand for common disorders. Our demonstration
that gain-of-function changes in mutant NaV1.7 channels cause inherited erythromelalgia (Cummins,
Dib-Hajj, and Waxman 2004; Dib-Hajj et al. 2005) and, following that, discovery that other gain-of-function
mutations of NaV1.7 cause pain in paroxysmal extreme pain disorder (PEPD) (Fertleman et
al. 2006), had shown that hyperactivity of NaV1.7 channels can produce disorders characterized by
intense pain. But these were very rare diseases, zebras. Might NaV1.7 be a player in chronic pain within
broader populations?...

GAIN OF FUNCTION NaV1.7 MUTATIONS IN IDIOPATHIC SMALL FIBER NEUROPATHY

Small nerve fiber neuropathy (SFN) is a relatively
common disorder of thinly myelinated and
unmyelinated nerve fibers recently recognized as
a distinct clinical syndrome.1
The clinical picture
is typically dominated by onset in adulthood of
neuropathic pain, often with a burning quality,
and autonomic symptoms.2–6
The diagnosis of
pure SFN, in which small diameter nerve fibers
are affected but large diameter fibers are spared,
is usually made on the basis of the clinical picture,
preservation of large fiber functions (normal
strength, tendon reflexes, and vibration sense),...

10 RIPPLES

One of the exciting things about science is that it can have an impact beyond what was expected.
Research on one project can inform research on another. This can occur because concepts or conclusions,
derived from one particular research effort, hold lessons for a second project; or because a new
tool or a new method, developed for one project, proves to be useful in a second project; or because
expertise accrued for one project turns out be relevant to a second. In some cases this ripple effect can
extend from one disease to another. This was the case in the search for a gene in a 15-year-old girl.
Analysis of her genes propelled us to use methods from our research on pain to help understand another
disorder. Her genes were, in fact, the centerpiece of a touching story....

IV MUTING GOD’S MEGAPHONE: FROM THE SQUID TOWARD THE CLINIC

11 SEVEN YEARS FROM THEORY TOWARD THERAPY … VIA “PAIN IN A DISH”

Discovering that the SCN9A gene and its NaV1.7 sodium channel play a key role in pain marked, in a
sense, a successful end of the search for a pain gene. I could have finished this book at that point. But
a larger quest was ahead. Science goes on and on, with the answer to each question raising new challenges
and suggesting new possibilities.
Turning a target—NaV1.7 in this instance—into a treatment is not easy. There is a lot of work to do
in the laboratory before a potential medicine even begins to be tested in humans. Then one must define
the appropriate people to test it in, and design the most informative trial. Human subjects with the
disease under study have to be located and enrolled. They have to be randomized into multiple groups,...

PHARMACOLOGICAL REVERSAL OF A PAIN PHENOTYPE IN iPSC-DERIVED SENSORY NEURONS AND PATIENTS WITH INHERITED ERYTHROMELALGIA

In common with other chronic pain conditions, there is an
unmet clinical need in the treatment of inherited erythromelalgia
(IEM). The SCN9A gene encoding the sodium
channel NaV1.7 expressed in the peripheral nervous
system plays a critical role in IEM. A gain-of-function
mutation in this sodium channel leads to aberrant sensory
neuronal activity and extreme pain, particularly in response
to heat. Five patients with IEM were treated with a new
potent and selective compound that blocked the NaV1.7
sodium channel resulting in a decrease in heat-induced
pain in most of the patients. We derived induced pluripotent
stem cell (iPSC) lines from four of five subjects and
produced sensory neurons that emulated the clinical phenotype
of hyperexcitability and aberrant responses to heat
stimuli. When we compared the severity of the clinical...

Even as NaV1.7 blockers were (and are) being developed, we were also taking another approach: using
the human genome to predict whether an existing medication would help a particular person. This
approach, variously called “precision medicine,” “personalized medicine,” or “individualized medicine,”
uses the DNA of each specific patient to give the clinician a molecular compass that points to
the most effective medication. Currently we do not have that molecular compass in pain medicine. The
clinician usually begins by selecting a particular medication, based on the patient’s description of the
pain, the cause of the pain or its pattern, and other aspects of the patient’s history. The most effective
medication, the dosage, and the dosing schedule can vary from patient to patient. The choice of...

Sodium channel NaV1.7 is critical for human pain signaling.
Gain-of-function mutations produce pain syndromes
including inherited erythromelalgia, which is usually
resistant to pharmacotherapy, but carbamazepine normalizes
activation of NaV1.7-V400M mutant channels from a
family with carbamazepine-responsive inherited erythromelalgia.
Here we show that structural modeling and thermodynamic
analysis predict pharmacoresponsiveness of
another mutant channel (S241T) that is located 159 amino
acids distant from V400M. Structural modeling reveals...

13 PRECISION

On January 30, 2015, President Barack Obama announced details of the Precision Medicine Initiative
(The White House 2015). In launching this initiative, the White House press briefing noted that “most
(currently available) medical treatments have been designed for the ‘average patient.’” The announcement
went on to describe an “approach to disease prevention and treatment that takes into account
individual differences in people’s genes” as well as environment and lifestyle.

Like many colleagues in the scientific community, my team and I at Yale were pleased to learn that
this initiative was moving forward. But, as we read the announcement we were bemused, for a very
specific reason: As the Precision Medicine Initiative was being discussed by policy makers in...

PHARMACOTHERAPY FOR PAIN IN A FAMILY WITH INHERITED ERYTHROMELALGIA GUIDED BY GENOMIC ANALYSIS AND FUNCTIONAL PROFILING

Inherited erythromelalgia (IEM) is an autosomal
dominant disorder characterized by severe
burning pain in the distal extremities, triggered
by warmth and relieved by cooling, caused by
gain-of-function mutations of the NaV1.7 sodium
channel, which is encoded by the SCN9A gene.1
NaV1.7 is preferentially expressed within peripheral
sensory dorsal root ganglion (DRG) and
sympathetic ganglion neurons,2–4
where it activates
at relatively hyperpolarized potentials below the threshold for action potential generation.
NaV1.7 amplifies small stimuli, thereby
setting the gain for firing.2
In general, the NaV1.7...

14 “THE IMPORTANT THING IS NOT TO STOP”

When NaV1.7 was identified as a major player in pain and mutations of its SCN9A gene were shown
to produce dramatic pain profiles in humans, a pain gene had been found. But science’s arrow never
stops flying. Sometimes it advances rapidly, and sometimes slowly. It is now whizzing ahead in laboratory
experiments that are teaching us how ion channels work and how their dysfunction can cause
disease. And, at the same time, it is slowly inching forward on another track, in studies on novel clinical
approaches—small molecule blockers, gene therapy strategies, inhibitors based on modified toxins or
antibodies—that will hopefully become new medications that put NaV1.7 to sleep....

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